Summary: Innate and adaptive immunities are the two major arms of the immune system, which rely on distinct cell types. These cells can be distinguished not only by the source of diversity for non-self recognition, of germline or somatic origin, but also by their localization and the pattern and rates of response after encounter of antigenic triggers. In addition, subsets of lymphocytes exist whose receptors require rearrangement but result in semi-invariant structures with a high degree of self-specificity. We hypothesized that these innate-like lymphocytes might share a common gene transcription signature that relates them to classic members of the innate immune system. This relationship was first observed in agonist-induced CD8αα T cells in fetal/neonatal thymus. We then asked whether this notion could be extended to other innate-like lymphocytes, by comparison of gene expression profiles of innate-like lymphocytes and closely paired adaptive system counterparts (NKT versus CD4T, CD8ααT versus CD8αβT, and B1 versus B2). A statistically significant ‘innate signature’ indeed was distilled. Particularly intriguing was the high representation of interferon-inducible guanosine triphophatases crucial for resistance against intracellular pathogens and of small G proteins involved in intracellular vacuole maturation and trafficking. Overall, this combined expression pattern can be designated as an innate signature among lymphocytes.